Regulation of chloride ion flux across cellular membranes is critical to maintaining homeostasis across epithelial membranes. Abnormal chloride (Cl−) ion flux can lead to several different pathophysiological conditions, including cystic fibrosis, polycystic kidney disease, etc. One of the most widespread diseases is diarrhea, in particular infectious secretory diarrhea, where chloride and water secretion are upregulated by cholera toxin or excessive prostaglandin secretion in response to inflammation. Of all enteric pathogens that produce diarrhea in humans, cholera toxin, which stimulates chloride ion and fluid secretion by permanently activating the enzyme adenylate cyclase and cAMP, induces the most rapidly fatal condition.
According to the WHO, diarrhea is one of the leading causes of death in the world, particularly in developing countries where bacterial contamination of food and water is widespread. The problem is especially severe in children and infants, with more than 5 million children under age of 5 dying annually from malnutrition, diarrhea, and dehydration. Most of the currently available antidiarrheal agents act as antiperistaltic agents to inhibit gastric motility and peristalsis, while some are adsorbents and antibacterial agents. None of these have been shown to inhibit electrolyte and fluid secretion which, in most severe cases, is the cause of diarrhea. Antiperistaltic agents may cause central nervous system side effects, as well as unwanted effects on the GI tract including nausea, vomiting and abdominal discomfort. Moreover, while quite a number of traditional Chinese medicines provide alternative treatments for diarrhea, their active ingredients are usually not defined and their mechanisms of action are not clear. Thus there is a need in the art for a therapeutic agent with known active ingredients which specifically modulates chloride and water secretion. The present invention fulfills this and other needs.